Cyanopyrroles

ABSTRACT

This invention provides a progesterone receptor antagonist of formula 1 having the structure  
                 
 
     wherein T is O, S, or absent; R 1 , and R 2  are each, independently, hydrogen, alkyl, substituted alkyl; or R 1  and R 2  are taken together form a ring and together contain —CH 2 (CH 2 ) n CH 2 —, —CH 2 CH 2 CMe 2 CH 2 CH 2 —, —O(CH 2 ) p CH 2 —, —O(CH 2 ) q O—, —CH 2 CH 2 OCH 2 CH 2 —, or —CH 2 CH 2 NR 7 CH 2 CH 2 —;  
     n=1-5; p=1-4; q=1-4;  
     R 3  is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A ;  
     R A  is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;  
     R 4  is hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;  
     R 5  is hydrogen, alkyl, or substituted alkyl;  
     R 6  is hydrogen, alkyl, substituted alkyl, or COR B ,  
     R B  is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;  
     R 7  is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. patent application Ser.No. 09/552,544, filed Apr. 19, 2000, which claims the benefit of thepriority of U.S. patent application Ser. No. 60/183,050, filed May 4,1999, now abandoned.

BACKGROUND OF THE INVENTION

[0002] Intracellular receptors (IR) form a class of structurally relatedgene regulators known as “ligand dependent transcription factors” (R. M.Evans, Science, 240, 889, 1988). The steroid receptor family is a subsetof the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

[0003] The natural hormone, or ligand, for the PR is the steroidprogesterone, but synthetic compounds, such as medroxyprogesteroneacetate or levonorgestrel, have been made which also serve as ligands.Once a ligand is present in the fluid surrounding a cell, it passesthrough the membrane via passive diffusion, and binds to the IR tocreate a receptor/ligand complex. This complex binds to specific genepromoters present in the cell's DNA. Once bound to the DNA the complexmodulates the production of mRNA and protein encoded by that gene.

[0004] A compound that binds to an IR and mimics the action of thenatural hormone is termed an agonist, whilst a compound that inhibitsthe effect of the hormone is an antagonist.

[0005] PR agonists (natural and synthetic) are known to play animportant role in the health of women. PR agonists are used in birthcontrol formulations, typically in the presence of an ER agonist,alternatively they may be used in conjunction with a PR antagonist. ERagonists are used to treat the symptoms of menopause, but have beenassociated with a proliferative effect on the uterus that can lead to anincreased risk of uterine cancers. Co-administration of a PR agonistreduces or ablates that risk.

[0006] Jones et al (U.S. Pat. No. 5,688,810) described the PR antagonistdihydroquinoline A.

[0007] Jones et al described the enol ether B (U.S. Pat. No. 5,693,646)as a PR ligand.

[0008] Jones et al described compound C (U.S. Pat. No. 5,696,127) as aPR ligand.

[0009] Zhi et al described lactones D, E and F as PR antagonists (J.Med. Chem. 41, 291, 1998).

[0010] Zhi et al described the ether G as a PR antagonist (J. Med. Chem.41, 291, 1998).

[0011] Combs et al disclosed the amide H as a ligand for the PR (J. Med.Chem. 38, 4880, 1995).

[0012] Perlman et al described the vitamin D analog I as a PR ligand(Tetrahedron. Lett. 35, 2295, 1994).

[0013] Hamann et al described the PR antagonist J (Ann. N.Y. Acad. Sci.761, 383, 1995).

[0014] Chen et al described the PR antagonist K (Chen et al, POI-37,16^(th) Int. Cong. Het. Chem, Montana, 1997).

[0015] Kurihari et al described the PR ligand L (J. Antibiotics 50, 360,1997).

[0016] Kuhla et al claimed the oxindole M as a cardiotonic (WO86/03749).

[0017] Weber claimed the oxindole N for cardiovascular indications (WO91/06545).

[0018] Fischer et al claim a preparation for making compounds whichinclude the generic structure O (U.S. Pat. No. 5,453,516).

[0019] Singh et al described the PDE III inhibitor P (J. Med. Chem. 37,248, 1994).

[0020] Andreani et al described the cytotoxic agent Q (Acta. Pharm.Nord, 2, 407, 1990).

[0021] Binder et al described structure R which is an intermediate forpreparing COX II inhibitors (WO 97/13767).

[0022] Walsh (A. H. Robins) described the oxindole S as an intermediate(U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566).

[0023] R₁=F, Cl, Br, alkyl, NH₂

[0024] R₂=alkyl, alkoxy, F, Cl, NH₂, CF₃

[0025] Bohm et al claim the oxindole T as cardiovascular agents (WO91/06545).

[0026] Bohm et al include the generic structure U (WO 91/04974).

[0027] A Japanese patent contains the generic structure V (JP 63112584A).

[0028] Boar et al described the dioxolane W as an intermediate forpreparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).

[0029] Kende et al described methodology for preparing 3,3-substitutedoxindoles, e.g., X, that was utilized in the present invention (Synth.Commun. 12, 1, 1982).

[0030] There are numerous literature reports that disclose a number ofbenzoxazin-2-ones. However, none of these examples in these patentscontain substituents necessary for the compounds to be active asprogesterone receptor modulators.

[0031] Among these publications, Narr et al (German Patent, DE 3633861,CA 109:22973) claimed that imidazobenzoxazinones, e.g. Y, ascardotonics; Benzoxazin-2-ones, such as brofoxine (Z), being active asan anxiolytic was reported by Hartmann et al (Proc. West. Pharmacol.Soc. 21, 51-55 (1978)). More recently, a number of patents (e.g., Younget al WO95/20389; Christ et al. WO98/14436) claimed quinazolin-2-onesand benzoxazin-2-ones such as compounds AA and BB as inhibitors of HIVreverse transcriptase.

DESCRIPTION OF THE INVENTION

[0032] This invention provides progesterone receptor agonists of Formula1 having the structure

[0033] wherein

[0034] T is O, S, or absent;

[0035] R₁, and R₂ are each, independently, hydrogen, alkyl, substitutedalkyl; or

[0036] R₁ and R₂ are taken together form a ring and together contain—CH₂(CH₂)_(n)CH₂—, —CH₂CH₂CMe₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—,—CH₂CH₂OCH₂CH₂—,or —CH₂CH₂NR₇CH₂CH₂—;

[0037] n=1-5;

[0038] p=1-4;

[0039] q=1-4

[0040] R₃ is hydrogen, OH, NH₂, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, or COR^(A);

[0041] R^(A) is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, aminoalkyl, or substituted arninoalkyl;

[0042] R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;

[0043] R₅ is hydrogen, alkyl, or substituted alkyl;

[0044] R₆ is hydrogen, alkyl, substituted alkyl, or COR^(B);

[0045] R^(B) is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, aminoalkyl, or substituted aminoalkyl;

[0046] R₇ is hydrogen or alkyl;

[0047] or a pharmaceutically acceptable salt thereof, which are usefulfor contraception, in the treatment of fibroids, endometriosis, breast,uterine, ovarian and prostate cancer, and post menopausal hormonereplacement therapy

[0048] Preferred compounds of this invention are those having thestructure:

[0049] wherein

[0050] T is O, or absent;

[0051] R₁, and R₂ are each, independently, hydrogen, alkyl, substitutedalkyl; or

[0052] R₁ and R₂ are taken together form a ring and together contain—CH₂(CH₂)_(n)CH₂—;

[0053] n=1-5;

[0054] R₃ is hydrogen;

[0055] R₄ is hydrogen or halogen;

[0056] R₅ is hydrogen or alkyl;

[0057] R₆ is hydrogen or alkyl;

[0058] or a pharmaceutically acceptable salt thereof

[0059] The compounds of this invention may contain an asymmetric carbonatom and some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereoisomers. While shown without respect to stereochemistry inFormula 1, the present invention includes such optical isomers anddiastereoisomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof

[0060] The compounds of this invention have been shown to act ascompetitive inhibitors of progesterone binding to the PR and act asagonists in functional models, either/or in-vitro and in-vivo. Thesecompounds may be used for contraception, in the treatment of fibroids,endometriosis, breast, uterine, ovarian and prostate cancer, and postmenopausal hormone replacement therapy.

[0061] The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1-6 carbonatoms; “alkenyl” includes both straight- and branched-chain alkyl groupsof 2-6 carbon atoms containing at least one carbon-carbon double bond;“alkynyl” group includes both straight- and branched-chain alkyl groupsof 2-6 carbon atoms with at least one carbon-carbon triple bond.

[0062] The terms “substituted alkyl”, “substituted alkenyl”, and“substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as containingone or more substituents from the group including halogen, CN, OH, NO₂,amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic,alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,alkylamino, arylthio. These substituents may be attached to any carbonof alkyl, alkenyl, or alkynyl group provided that the attachmentconstitutes a stable chemical moiety.

[0063] The term “thioalkyl” is used herein to refer to the SR group,where R is alkyl or substituted alkyl.

[0064] The term “alkoxy” is used herein to refer to the OR group, whereR is alkyl or substituted alkyl.

[0065] The term “aryloxy” is used herein to refer to the OR group, whereR is aryl or substituted aryl.

[0066] The term “alkylcarbonyl” is used herein to refer to the RCOgroup, where R is alkyl or substituted alkyl.

[0067] The term “alkylcarboxy” is used herein to refer to the COORgroup, where R is alkyl or substituted alkyl. This term is also referredto as alkoxycarbonyl.

[0068] The term “aminoalkyl” refers to both secondary and tertiaryamines wherein the alkyl or substituted alkyl groups may be either sameor different and the point of attachment is on the nitrogen atom.

[0069] The term “halogen” is defined as Cl, Br, F, and I.

[0070] Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids. Salts may also beformed from inorganic bases, preferably alkali metal salts, for example,sodium, lithium, or potassium, and organic bases, such as ammonium,mono-, di-, and trimethylammonium, mono-, di- and triethylammonium,mono-, di- and tripropyl-ammonium (iso and normal),ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpho-linium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methyl-piperidinium, 1-ethyl-2-methylpiperidinium,mono-, di- and triethanolammonium, ethyl diethanolammonium,n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-ammonium,phenylmonoethanolammonium, and the like.

[0071] The compounds of this invention were be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using literature procedures.These schemes show the preparation of representative compounds of thisinvention.

[0072] According to scheme 1, commercially available oxindole 4 istreated with a strong organo-metallic base (e.g., butyl lithium, lithiumdiisopropylamide, potassium hexamethyldisilazide) in an inert solvent(e.g. THF, diethyl ether) under nitrogen at reduced temperature (ca.−20° C.) (Kende, et al, Synth. Commun. 12, 1, 1982). The resultingdi-anion then is treated with excess electrophile such as an alkylhalide, preferably an iodide. If R₁ and R₂ are to be joined such as theproduct 5 contains a spirocycle at position 3, then the electrophileshould be bifunctional, i.e. a diiodide. Subsequent bromination of 5proceeds smoothly with bromine in acetic acid (an organic co-solventsuch as dichloromethane may be added as required) in the presence ofsodium acetate, to afford the aryl bromide 6. The bromide 6 is reactedwith a palladium salt (e.g., tetrakis(triphenylphoshine)palladium(0) orpalladium acetate), in a suitable solvent (e.g., THF, dimethoxyethane,acetone, ethanol or toluene) at room temperature under an inertatmosphere (argon, nitrogen). The mixture is then treated with pyrrole2-boronic acid (Synthesis 613, 1991) and a base (potassium carbonate,triethylamine, potassium phosphate) in water or fluoride source (cesiumfluoride) under anhydrous conditions. Treatment of the biaryl compound 7with chlorosulfonyl isocyanate followed by an excess of DMF at lowtemperature produces the protected cyanopyrrole 8. Removal of thetert-butyloxycarbonyl (BOC) protecting group via standard conditions(e.g., TFA/dichloromethane, aqueous NaOH, thermolysis) produces therequired final product which is purified by standard means.

[0073] As depicted in Scheme 2, an appropriately substituted ortho-aminobenzoic acid, or derivative (such as ethyl ester) 10 is treated with asuitable organometallic reagent, e.g., Grignard reagent, in appropriatenonprotic solvents (e.g., THF, ether, toluene) under an inert atmospheresuch as argon or nitrogen at −78° C. to room temperature to giveortho-amino carbinol 11. Ring closure of carbinol 11 to yieldbenzoxazin-2-ones 12 is commonly effected by a condensing agent (e.g.,carbonyldiimidazole, phosgene, dimethylcarbonate, diethylcarbonate) in asuitable nonprotic solvent (e.g., THF, ether, toluene) at temperaturesin the range of room temperature to 65° C. The pyrrole ring is attachedto this platform by employing a suitable coupling reaction (e.g.,Suzuki, Stille) to give the biaryl 13. These reactions are performed inthe presence of suitable catalyst (e.g., palladium or nickel complexesoften with phosphino ligands, e.g., Ph₃P, dppf, dppe or palladium saltssuch as palladium acetate) and a base: the commonly used bases include(but are not limited to) sodium bicarbonate, sodium carbonate, potassiumphosphate, barium carbonate, potassium acetate, or cesium fluoride. Themost commonly used solvents in these reactions include benzene, DMF,isopropanol, ethanol, DME, ether, acetone or a mixture of any one ofthese solvent and water. The coupling reaction generally is executedunder an inert atmosphere such as nitrogen or argon at temperaturesranging from room temperature to 95° C. Treatment of the biaryl compound13 with chlorosulfonyl isocyanate followed by an excess of DMF at lowtemperature produces the protected cyanopyrrole 14. Removal of thetert-butyloxycarbonyl (BOC) protecting group via standard conditions(e.g., TFA/dichloromethane, aqueous NaOH, thermolysis) produces therequired final product 15 which is purified by standard means.

[0074] The compounds of this invention are progestational agonists, andare therefore useful as oral contraceptives (male and female), inhormone replacement therapy (particularly when combined with anestrogen), in the treatment of endometriosis, luteal phase defects,benign breast and prostatic diseases and prostatic, breast, ovarian,uterine and endometrial cancers.

[0075] The compounds of this invention can be used alone as a soletherapeutic agent or can be used in combination with other agents, suchas other estrogens, progestins, or androgens.

[0076] The compounds of this invention can be formulated neat or with apharmaceutical carrier for administration, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmacological practice. Thepharmaceutical carrier may be solid or liquid.

[0077] A solid carrier can include one or more substances which may alsoact as flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders, thecarrier is a finely divided solid which is in admixture with the finelydivided active ingredient. In tablets, the active ingredient is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

[0078] Liquid carriers are used in preparing solutions, suspensions,emulsions, syrups, elixirs and pressurized compositions. The activeingredient can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, a mixtureof both or pharmaceutically acceptable oils or fats. The liquid carriercan contain other suitable pharmaceutical additives such assolubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoringagents, suspending agents, thickening agents, colors, viscosityregulators, stabilizers or osmo-regulators. Suitable examples of liquidcarriers for oral and parenteral administration include water (partiallycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,lethicins, and oils (e.g. fractionated coconut oil and arachis oil). Forparenteral administration, the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usefulin sterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

[0079] Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compounds of this invention can also beadministered orally either in liquid or solid composition form

[0080] The compounds of this invention may be administered rectally orvaginally in the form of a conventional suppository. For administrationby intranasal or intrabronchial inhalation or insufflation, thecompounds of this invention may be formulated into an aqueous orpartially aqueous solution, which can then be utilized in the form of anaerosol. The compounds of this invention may also be administeredtransdermally through the use of a transdermal patch containing theactive compound and a carrier that is inert to the active compound, isnon toxic to the skin, and allows delivery of the agent for systemicabsorption into the blood stream via the skin. The carrier may take anynumber of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments may be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient may also besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semipermeable membranecovering a reservoir containing the active ingredient with or without acarrier, or a matrix containing the active ingredient. Other occlusivedevices are known in the literature.

[0081] The dosage requirements vary with the particular compositionsemployed, the route of administration, the severity of the symptomspresented and the particular subject being treated. Based on the resultsobtained in the standard pharmacological test procedures, projecteddaily dosages of active compound would be 0.02 μg/kg-750 μg/kg.Treatment will generally be initiated with small dosages less than theoptimum dose of the compound. Thereafter the dosage is increased untilthe optimum effect under the circumstances is reached; precise dosagesfor oral, parenteral, nasal, or intrabronchial administration will bedetermined by the administering physician based on experience with theindividual subject treated. Preferably, the pharmaceutical compositionis in unit dosage form, e.g. as tablets or capsules. In such form, thecomposition is sub-divided in unit dose containing appropriatequantities of the active ingredient; the unit dosage forms can bepackaged compositions, for example, packaged powders, vials, ampoules,pre filled syringes or sachets containing liquids. The unit dosage formcan be, for example, a capsule or tablet itself, or it can be theappropriate number of any such compositions in package form.

[0082] The following provides the preparation of representativecompounds of this invention.

EXAMPLE 1 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1H-pyrrole-2-carbonitrile

[0083] A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dryTHF (200 mL) was treated at −78° C. under nitrogen with a solution ofmethylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reactionmixture was slowly warmed to ambient temperature, kept stirring for 48hours under nitrogen and then poured into a cold 0.5 N aqueoushydrochloride solution (300 mL). The mixture was neutralized withaqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) wasadded. The organic layer was separated and aqueous layer was extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith brine and dried (MgSO₄). After removal of solvent in vacuo, theresidue was purified by a silica gel flash chromatography (hexane:ethylacetate/3:2) to give 2-(2-amino-5-bromophenyl) propan-2-ol as anoff-white solid (6 g, 57%): mp 62-63° C.; ₁H-NMR (CDCl₃) δ 7.19 (d, 1H,J=2.3 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70(s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).

[0084] To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78mmol) in dry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94mmol) under nitrogen. The reaction solution was heated at 50° C.overnight. The solvent was removed in vacuo and the residue wasdissolved in ethyl acetate (100 mL). The solution was washed with 1Naqueous hydrochloride solution (2×40 mL), brine (20 mL), and dried withMgSO₄. After removal of the solvent in vacuo,6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d][1,3]oxazin-2-one was obtainedas a white solid (20 g, 100%): mp 199-200° C.; ¹H-NMR (DMSO-d₆) δ 10.32(s, 1H, D₂O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5,2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H).

[0085] A solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (5.0 g, 20 mmol) andtetrakis(triphenylphosphine)palladium(0) (580 mg, 0.5 mmol) in toluene(200 mL) was stirred under a flow of nitrogen for 25 min. To thesolution was added sequentially 1-tert-butoxycarbonylpyrrole-2-boronicacid (8.24 g, 39 mmol) in absolute ethanol (50 mL) and potassiumcarbonate (5.39 g, 39 mmol) in water (50 mL). The mixture was heated to80° C. for 16 h and allowed to cool. The reaction mixture was pouredinto aqueous saturated sodium bicarbonate solution (200 mL) andextracted with ethyl acetate (3×200 mL). The organic layers werecombined, washed with water (200 mL) and brine (100 mL) and dried overmagnesium sulfate. The solution was filtered, concentrated in vacuo, andthe residue was purified by flash column chromatography on silica gel(30% ethyl acetate/hexane) to give2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (4.0 g, 58%) asa tan solid, mp 172-173° C.

[0086] To a solution of 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3] oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (2.0 g,5.8 mmol) in THF (anhydrous, 50 mL) at −78° C. was added chlorosulfonylisocyanate (0.66 mL, 6.7 mmol). After 90 min, DMF (9 mL, 116 mmol) wasadded and the reaction was allowed to warm to room temperature. Thereaction mixture was poured into water (50 mL) and extracted with ethylacetate (2×50 mL). The organic layers were combined, washed with brine(50 mL), dried over magnesium sulfate, filtered and concentrated invacuo. Purification via flash column chromatography on silica gel (30%ethyl acetate/hexane) gave 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [1,3] oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butylester (1.1 g, 52%) as a white powder, mp 165-167° C. ¹H NMR (d₆-DMSO,300 MHz) δ 1.36 (s, 9H), 1.61 (s, 6H), 6.44 (d, 1H, J=3.7 Hz), 692 (d,1H, J=8.2 Hz), 7.27-7.32 (m, 2H) (‘d’, 1H, J=1.5 Hz), 10.36 (s, 1H). MS(EI) m/z 367 [M]⁺.

[0087] 2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1 g,2.7 mmol) was placed in a 25 mL round bottomed flask stoppered with arubber septum and equipped with a nitrogen inlet and a needle to allowgaseous outflow. A vigorous flow of nitrogen was maintained as the flaskwas placed in an oil bath and heated to 160° C. After 20 min at thistemperature, the flask was removed from the oil bath and allowed tocool. The yellow residue was washed into a larger flask withdichloromethane/ethyl acetate and adsorbed onto a small amount of silicagel. Purification by flash column chromatography on silica gel (40%ethyl acetate/hexane) gave the title compound (340 mg, 47%) as a yellowpowder, mp 241-242° C. ¹H NMR (d₆-DMSO, 300 MHz) δ 1.65 (s, 6H), 6.67(d, 1H, J=3.9 Hz), 6.91 (d, 1H, J=8.3 Hz), 6.98 (d, 1H, J=3.9 Hz), 7.61(dd, 1H, J=1.8, 8.3 Hz), 7.65 (‘d’, 1H, J=1.6 Hz), 10.32 (s, 1H), 12.54(bs, 1H). MS (EI) m/z 267 M⁺. Anal. Calcd. For C₁₅H₁₃N₃O₂: C, 67.41; H,4.90; N, 15.72. Found: C, 67.19; H, 4.96; N, 15.35.

EXAMPLE 2 5-(2′-Oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol ]-5′-yl-2-cyanopyrrole

[0088] A solution of oxindole (25 g, 0.19 mol) in anhydroustetrahydrofuran (800 mL) was cooled to −20° C., then n-butyllithium(2.5M in hexanes, 152 mL, 0.38 mol) was added slowly followed byN,N,N′,N′-tetramethylethylenediamine (51 mL, 0.38 mol,). After 15 min.1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture wasallowed to warm to room temperature. After stirring for 16 h saturatedaqueous ammonium chloride solution (1L) and EtOAc (1L) were added. After15 min. the layers were separated and the aqueous phase was extractedusing EtOAc (×2). The combined organic layers were extracted withhydrochloric acid (1N), then washed with brine (500 mL), dried (MgSO₄),and concentrated to obtain an oil. The oil was triturated with hexane(200 mL) and benzene (20 mL). The precipitate was collected and dried invacuo to obtain spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one (26.3 g,69.6%) as colorless crystals: mp 110-114° C.; ¹H NMR (DMSO-d₆) δ 1.67(m, 10H), 6.84 (d, 1H, J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8Hz), 7.44 (d, 1H, J=8 Hz), 10.3 (s, 1H).

[0089] To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(17.6 g, 9 mmol) in acetic acid (300 mL) was added sodium acetate (8.0g, 0.1 mol) and bromine (14.6 g, 91 mmol) with stirring. After 30 min.at room temperature, the reaction mixture was partitioned between waterand EtOAc. The aqueous phase was extracted twice with EtOAc. Thecombined organic layers were washed with water, dried (MgSO₄) andevaporated and the residue was triturated with hexane. The precipitatewas collected, and dried in vacuo to obtain5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1H)-one (16.5 g, 67%) asoff-white crystals: mp 196-199° C.; ¹H NMR (DMSO-d₆) δ 1.62 (m, 10H),6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz) 7.58 (dd, 1H, J=8.2,1.8 Hz), 10.44 (s, 1H).

[0090] To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one(3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere, wasadded tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq,3.31 g, 15.6 mmol) and a solution of K₂CO₃ (2.3 eq, 3.83 g, 27.6 mmol)in water (5 mL) were added sequentially. The solution was heated to 80°C. for 3 h and allowed to cool. The reaction mixture was poured intowater (200 mL) and extracted with EtOAc (2×100 mL). The organic layerswere combined, washed with brine (150 mL) and dried over MgSO₄. Thesolution was filtered, concentrated in vacuo, and the residue waspurified by flash column chromatography on silica gel (eluting with 30%EtOAc/hexane) to give2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol ]-5 ′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a whitepowder, mp 177° C. ¹H NMR (CDCl₃;300 MHz) δ 1.38 (s, 9 H), 1.59-1.93 (r,10H), 6.18 (m, 1H), 6.23 (‘t’, 1H, 3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d,1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D₂Oex). MS((+)-APCI) m/z 367 [(M+H)⁺]. Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H,7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.

[0091] To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (0.75 g, 2 mmol)in THF (anhydrous, 20 mL) at −78° C. was added chlorosulfonyl isocyanate(1.15 eq, 0.23 mL, 2.3 mmol). After 90 min, DMF (20 eq, 3.6 mL, 46 mmol)was added and the reaction was allowed to warm to room temperature. Thereaction mixture was poured into water (50 mL) and extracted with ethylacetate (2×50 mL). The organic layers were combined, washed with brine(50 mL), dried over magnesium sulfate, filtered and concentrated invacuo. Purification via flash column chromatography on silica gel (30%ethyl acetate/hexane) gave5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylic acid, tert-butyl ester (0.5 g, 63%)as an oil which crystallized from acetone to give white crystals, mp156° C. ¹H NMR (d₆-DMSO, 400 MHz) δ 1.32 (s, 9H), 1.50 (m, 3H),1.60-1.70 (m, 5 H), 1.75-1.85 (m, 2H), 6.38 (d, 1H, J=3.7 Hz), 6.87 (d,1H, J=7.9 Hz), 7.18 (dd, 1H, J=1.5, 7.9 Hz), 7.27 (d, 1H, J=3.7 Hz),7.48 (d, 1H, J=1.8 Hz), 10.42 (bs, 1H). MS (EI) m/z 391 (M⁺). Anal.Calcd for C₂₃H₂₅N₃O₃: C, 70.57; H, 6.44; N, 10.73. Found: C, 69.82; H,6.46; N, 10.43.

[0092]5-(2′-Oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylic acid, tert-butyl ester (0.25 g, 0.8mmol) was placed in a 5 mL round bottomed flask stoppered with a rubberseptum and equipped with nitrogen inlet and a needle to allow gaseousoutflow. A vigorous flow of nitrogen was maintained as the flask wasplaced in an oil bath and heated to 180° C. After 5 min at thistemperature, the flask was removed from the oil bath and allowed tocool. The black residue was washed into a larger flask with acetone andadsorbed onto a small amount of silica gel. Purification by flash columnchromatography on silica gel (eluting with 30% EtOAc/hexane) gave thetitle compound (95 mg, 51%) as a yellow oil which crystallized fromdichloromethane to give a grey powder, mp 239° C. (dec). ¹H NMR(DMSO-d₆;300 MHz) δ 1.40-1.90 (m, 10H), 6.60 (m, 1H), 6.88 (d, 1H, J=8.1Hz), 6.95 (m, 1H), 7.56 (dd, 1H, J=1.8, 8.1 Hz), 7.78 (d, 1H, J=1.3 Hz),10.42 (s, 1H), 12.50 (s, 1H). MS (EI) m/z 291 (M⁺). Anal. Calcd forC₁₈H₁₇N₃O₁: C, 74.20; H, 5.88; N, 14.42. Found: C, 66.63; H, 5.52; N,12.46.

EXAMPLE 32-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole

[0093] To a solution2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester (0.39 g, 1.2 mmol) in THF (anhydrous, 9 mL) at−78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.12 mL, 1.4mmol). After 120 min, DMF (20 eq, 1.8 mL, 23 mmol) was added and thereaction was allowed to warm to room temperature. The reaction mixturewas poured into water (25 mL) and extracted with ethyl acetate (2×50mL). The organic layers were combined, washed with brine (50 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationvia flash column chromatography on silica gel (1:3 ethyl acetate/hexane)gave2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole-1-carboxylicacid tert-butyl ester (0.21 g, 50%) as a white solid: mp 158.6. ¹H NMR(DMSO-d₆; 300 MHz) δ 1.27 (s, 6H), 1.33 (s, 9H), 6.40 (d, 1H, J=3.8 Hz),6.90 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H, J=1.8, 8.0 Hz), 7.30 (d, 1H, J=1.5Hz), 10.50 (s, 1H). MS m/z 350 (M−H)⁻. Calcd for C₁₉H₂₂N₂O₃: C, 68.36;H, 6.02; N, 11.96. Found: C, 66.79; H, 6.03; N, 11.02.

[0094]2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester (0.18 g, 0.51 mmol) was placed in a 50 mL roundbottomed flask stoppered with a rubber septum and equipped with anitrogen inlet and a needle to allow gaseous outflow. A vigorous flow ofnitrogen was maintained as the flask was placed in an oil bath andheated to 160° C. After 10 min at this temperature, the flask wasremoved from the oil bath and allowed to cool. The black residue waswashed into a larger flask with acetone and adsorbed onto a small amountof flurosil. Purification by flash column chromatography on silica gel(eluting with 1:3 acetone: hexane) gave the title compound (118 mg, 92%)as a white solid mp 255.9-257.9° C. ¹H NMR (DMSO-d₆;300 MHz) δ 1.29 (s,6H), 6.60 (m, 1H), 6.89 (d, 1H, J=8.0 Hz),6.96 (m, 1H), 7.55 (dd, 1H,J=1.4, 8.1 Hz), 7.69 (bs, 1H), 10.47 (s, 1H), 12.48 (s, 1H). MS m/z 250(M−H)⁻. Calcd for C₂₀H₂₁N₃O₃: C, 71.7; H, 5.21; N, 16.72. Found: C,71.16; H, 5.58; N, 16.09.

EXAMPLE 4 5-(2′-Oxo-2′,3′-dihydrospiro [cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole

[0095] A solution of 5′-bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (2.0 g, 7.5 mmol) andtetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in ethyleneglycol dimethyl ether (50 mL) was stirred under a flow of nitrogen for15 min. To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassiumcarbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to80° C. for 3 h and allowed to cool. The reaction mixture was poured intowater (50 mL) and extracted with ethyl acetate (3×50 mL). The organiclayers were combined, washed with brine (30 mL) and dried over magnesiumsulfate. The solution was filtered and concentrated in vacuo.Crystallization from 20% ethyl acetate/hexane gave2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol]-5′yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as awhite powder, mp 179-180.5° C. ¹H NMR (DMSO-d₆, 400 MHz) δ 1.30 (s, 9H),1.75-1.98 (m, 8 H), 6.16 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1H, J=3.3,3.3 Hz), 6.79 (d, 1H, J=7.9 Hz), 7.08 (dd, 1H, J=1.8, 7.9 Hz), 7.14(‘d’, 1H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz),10.30 (s, 1H). MS (EI) m/z352 [M⁺]. Anal. Calcd for C₂₁H₂₄N₂O₃: C, 71.57; H, 6.86; N, 7.95. Found:C, 71.08; H, 6.83; N, 7.74.

[0096] To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g,6.0 mmol) in THF (anhydrous, 25 mL) was added at −78° C. chlorosulfonylisocyanate (0.63 mL, 7.0 mmol). After 90 min, dimethylformamide (11 mL,140 mmol) was added and the reaction was allowed to warm to roomtemperature. The reaction mixture was poured into water (50 mL) andextracted with ethyl acetate (2×50 mL). The organic layers werecombined, washed with brine (50 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flash columnchromatography on silica gel (30% ethyl acetate/hexane) gave5-(2′-oxo-2,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxyic acid,tert-butyl ester (1.7 g, 75%) as white crystals, mp 167-169° C. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8 H), 6.39 (d, 1H,J=3.7 Hz), 6.84 (d, 1H, J=7.9 Hz), 7.17 (dd, 1H, J=1.8, 7.9 Hz), 7.28(‘t’, 2H), 10.41 (s, 1H). MS (ESI) m/z 376 [M-H]⁻. Anal. Calcd forC₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N,11.04.

[0097] 5-(2′-Oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylic acid, tert-butyl ester (1 g, 2.7mmol) was placed in a 25 mL round bottomed flask stoppered with a rubberseptum and equipped with nitrogen inlet and a needle to allow gaseousoutflow. A vigorous flow of nitrogen was maintained as the flask wasplaced in an oil bath and heated to 165° C. After 20 min at thistemperature, the flask was removed from the oil bath and allowed tocool. Crystallization from ethyl ether gave the title compound (600 mg,79%) as a yellow powder, mp 285-286° C. ¹H NMR (DMSO-d₆, 400 MHz) δ1.75-2.03 (m, 8 H), 6.60 (dd, 1H, J=2.4, 3.7 Hz), 6.84 (d, 1H, J=8.1Hz), 6.94 (dd, 1H, J=2.4, 3.7 Hz), 7.52 (dd, 1H, J=1.8, 8.1 Hz), 7.60(d, 1H, J=1.8 Hz), 10.38 (s, 1H), 12.45 (s, 1H). MS (ESI) m/z 276[M-H]⁻. Anal. Calcd. For C₁₇H₁₅N₃O: C, 73.63; H, 5.45; N, 15.15. Found:C, 73.24; H, 5.34; N, 14.96.

EXAMPLE 55-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2carbonitrile

[0098] To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (1 eq, 71 mg, 0.27 mmol) indimethylformamide (0.5 mL) was added potassium carbonate (5 eq, 0.18 g,0.1.35 mmol). After 10 min., iodomethane (3 eq, .05 mL, 0.81 mmol) wasadded and the suspension was stirred for 2h, poured into water (5 mL)and extracted with ethyl acetate (3×5 mL). The layers were separated,the aqueous layer was extracted with ethyl acetate (3×10 mL) and thecombined organic layer was washed with brine, dried over MgSO₄ andpurified by flash column chromatography on silica gel eluting with 30%ethyl acetate/hexane to give5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(30 mg, 41%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H),3.71 (s, 3H), 6.33 (d, 1H, J=4.1 Hz), 6.98 (d, 1H, J=8.0 Hz), 7.03 (d,1H, J=4.1 Hz), 7.39 (m, 2H), 10.39 (s, 1H). MS (APCI (−)) m/z 280(M−H)⁻. Anal. calcd for C₁₆H₁₅N₃0₂, C, 68.3, H, 5.37, N, 14.9. Found, C,68.4, H, 5.51, N, 14.6.

EXAMPLE 6 General Method A 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-31-benzoxazin-6-yl)-1-ethyl-1H-pyrrole-2-carbonitrile

[0099] To a solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(1.3 g, 5 mmol) in dimethylformamide (25 ml) was added potassiumcarbonate (1 g, 7.5 mmol), and iodoethane (0.4 ml, 5.1 mmol), and themixture was stirred at room temperature for 3 hours. Ethylacetate andwater were added, the ethylacetate layer was separated, dried overmagnesium sulfate, and concentrated in vacuo. The residue wasrecrystallized from ethylacetate/hexane to afford the title compound,m.p. 200-202° C. (0.4 g, 27%); ¹H-NMR (DMSO-d₆) δ 1.25 (t, J=7.2 Hz,3H), 1.64 (s, 6H), 4.07 (q, J=7.2 Hz, 2H), 6.29 (d, J=4.1 Hz, 1H), 7.0(d, J=8 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.34 (m, 2H), 10.42 (s, 1H).(−)) m/z 294 (M−H)⁻

EXAMPLE 75-(4,4-dimethyl-2-oxo-1,4-Dihydro-2H-3,1-benzoxazin-6-yl)-1-prop-2-ynyl-1H-pyrrole-2-carbonitrile

[0100]5-(4,4-Dimethyl-2-oxo-1,4,dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(0.74 g, 2.8 mmol) and propargylbromide (0.5 g, 4.2 mmol) were reacted,according to General Method A, to afford the title compound, m.p.222-224° C. (0.13 g, 15%). ¹H-NMR (DMSO-d₆) δ 1.65 (s, 6H), 3.64 (t,J=2.3 Hz, 1H), 4.85 (d, J=2.3 Hz, 2H), 6.37 (d, J=4 Hz, 1H), 7.01 (d,J=8.2 Hz, 1H), 7.11 (d, J=4 Hz, 1H), 7.43 (m, 2H), 10.45 (s, 1H), MS(APCI (−)) m/z 304 (M−H)⁻

EXAMPLE 8tert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-yl]acetate

[0101]5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile(5.4 g, 20 mmol) and tert-butylbromoacetate (4.64 g, 22 mmol) werereacted, according to General Method A, to afford the title compound,m.p. 188-190° C. (3 g, 40%). ₁H-NMR (DMSO-d₆) δ 1.35 (s, 9H), 1.62 (s,6H), 4.8 (s, 2H), 6.35 (d, J=4.3 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09(d, J=4.3 Hz, 1H), 7.26 (m, 2H), 10.42 (s, 1H), MS (APCI (−)) m/z 380(M−H)−

EXAMPLE 9[2-Cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]aceticacid

[0102] A solution oftert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetate(2.2 g, 5.8 mmol), and sodium hydroxide (1.6 g, 40 mmol) in ethanol (200ml) was heated to reflux for 2 hours. After cooling to room temperaturethe mixture was acidified with diluted hydrochloric acid, and extractedwith ethylacetate. The ethylacetate solution was dried over magnesiumsulfate, filtered, and concentrated in vacuo. Recrystallization fromethylacetate/hexane afforded the title compound, m.p. 207-209° C. (1.2g, 64%); ¹H-NMR (DMSO-d₆) δ 1.61 (s, 6H), 4.77 (s, 2H), 6.35 (d, J=4 Hz,1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, j=4.1 Hz, 1H), 7.26 (m, 2H), 10.43(s, 1H), MS (APCI (−)) m/z 324 (M−H)⁻.

EXAMPLE 102-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-I-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]acetamide

[0103] A solution of[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]aceticacid (0.6 g, 1.8 mmol), 3-ethoxy-4-methoxyphenylethylamine (0.36 g, 1.9mmol), diiso-propylethylamine (0.26 g, 2 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (0.7 g, 1.8 mmol) in dimethylformamide (20 ml) wasstirred at room temperature for 20 hours. The mixture was diluted withwater and extracted with ethylacetate. The ethylacetate solution waswashed with brine, dried over magnesium sulfate, and concentrated invacuo. The residue was recrystallized from ethanol to afford the titlecompound, mp. 160-162° C. (0.2 g, 22%): ¹H-NMR (DMSO-d₆) δ 1.3 (t, J=6.9Hz, 3H), 1.59 (s, 6H), 2.61 (t, 2H, J=7 Hz), 3.29 (q, J=6.9 Hz, 2H),3.71 (s, 3H), 3.97 (q, J=6.9 Hz, 2H), 4.6 (s, 2H), 6.32 (d, J=5.1 Hz,1H), 6.65 (dd, J=7.6, 2.0 Hz, 1H), 6.77 (d, J=2.3, 1H), 6.83 (d, J=8.3Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.26 (m, 2H),8.3 (t, J=6 Hz, 1H), 10.42 (s, 1H), MS (APCI (+)) m/z 503 (M+H)+

EXAMPLE 115-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1-pentyl-1H-pyrrole-2-carbonitrile

[0104]5-(4,4-Dimethyl-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrrole-carbonitrile(1.94 g, 7.3 mmol) was reacted, according to General Method A, with1-iodopentane (1.5 g, 7.6 mmol) to afford the title compound, m.p.128-131° C. (0.2 g, 8%); ¹H-NMR (DMSO-d₆) δ 0.73 (t, J=7.3 Hz, 3H), 1.05(m, 2H), 1.14 (m, 2H), 1.57 (m, 2H), 1.63 (s, 6H ), 4.04 (t, J=7.5 Hz,2H), 6.28 (d, J=4 Hz, 1H), 698 (d, J=7.9 Hz, 1H), 7.04 (d, J=4.5 Hz,1H), 7.33 (dd, J=8.9, 2.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 10.41 (s,1H), MS (APCI (−)) m/z 336 (M−H)⁻

EXAMPLE 125-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitriletert-Butyl2-cyano-5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate.

[0105] To a solution of 2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3] oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester(0.5 g, 1.4 mmol, 1 eq) in DMF (anhydrous, 25 mL) was added NaH (60%dispersion in oil, 65 mg, 1.6 mmol, 1.2 eq) at 0° C. After 15 min,methyl iodide (0.25 mL, 4.1 mmol, 3 eq) was added and the reaction wasallowed to warm to room temperature over night. The reaction mixture waspoured into water (50 mL) and extracted with ethyl acetate (2×50 mL).The organic layers were combined, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to give theproduct (0.5 g, 94%) as an off-white solid, mp 143-145° C.: ¹H NMR (300MHz, d6-DMSO) δ 1.38 (s, 9H), 1.62 (s, 6H), 3.33 (s, 3H), 6.48 (d, 1H,J=3.8 Hz), 7.13-7.16 (‘dd’, 1H), 7.33 (d, 1H, J=3.8 Hz), 7.40-7.43 (m,2H). MS (ESI (+)) [M+H]⁺=382. Anal. calcd. for C₂₁H₂₃N₃O₄: C, 66.13; H,6.08; N, 11.02. Found: C, 65.46; H, 6.16, N, 11.02.

[0106] tert-Butyl2-cyano-5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate(180 mg, 0.47 mmol) was placed in a 25 mL round bottomed flask stopperedwith a rubber septum and equipped with nitrogen inlet and a needle toallow gaseous outflow. A vigorous flow of nitrogen was maintained as theflask was placed in an oil bath and heated to 150° C. After 20 min atthis temperature, the flask was removed from the oil bath and allowed tocool. To the solid was added acetone/dichloromethane. The solid wasfiltered to give the product (100 mg, 76%) as an off-white solid, mp256-7° C. (dec.): ¹H NMR (300 MHz, d₆-DMSO) δ 1.65 (s, 6 H), 3.33 (s,3H), 6.74 (dd, 1H, J=2.6, 3.6 Hz), 7.00 (dd, 1H, J=2.2, 3.8 Hz), 7.15(d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=1.9 Hz), 7.73 (dd, 1H, J=1.9, 8.5 Hz),12.62 (s, 1H). MS (ESI (+)) [M+H]⁺=282. Anal. calcd. for C₁₆H₁₅N₃O₂: C,68.31;H,5.37; N, 14.94. Found: C, 67.87; H, 5.42, N, 14.75.

EXAMPLE 134-Bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile

[0107] To a solution of tert-butyl6-(5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate(1 eq, 1.94 g, 5.10 mmol) in THF (150 mL) at −78° C. was addedN-bromosuccinimide (1.1 eq, 1.0 g, 5.61 mmol). The solution was allowedto warm and stir for 16 hours Pyridine (1 mL) was added and the mixturewas poured into water (150 mL), the layers were separated, the aqueouslayer was extracted with ethyl acetate (3×10 mL) and the combinedorganic layer was washed with brine, dried over MgSO₄ and concentratedin vacuo. The product, tert-butyl6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylatewas obtained by crystallization from 20% ethyl acetate/hexane as a whitecrystalline solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.56 (s, 9H), 1.71 (s,6H), 3.65 (s, 3H), 7.30 (s, 1H), 7.44 (d, 1H, J=8.4 Hz), 7.52 (d, 1H,J=8.4 Hz), 7.55 (s, 1H). M/z (ESI (+)) 461 (M+H)⁺. Anal. calcd forC₂₁H₂₂N₃O₄, C, 54.8,H, 4.82, N, 9.13. Found, C, 54.9, H, 4.86, N, 9.1.

[0108] A solution of tert-butyl6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate(1 eq, 0.4 g, 0.87 mmol) in THF was added to a solution of sodiumethoxide (3 eq, 0.18 g, 2.6 mmol) in ethanol (10 mL). The solution washeated at 80° C. for 1 h then cooled to room temperature andconcentrated in vacuo. The residue was dissolved in THF (10 mL) and 4NHCl (10 mL) was added. After heating to 60° C. for 16 h the solution wascooled, poured into water and the layers were separated. The aqueouslayer was extracted with ethyl acetate (3×10 mL) and the combinedorganic layer was washed with brine, dried over MgSO₄ and concentratedin vacuo. The product,4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(0.17 g, 54%) was obtained by crystallization from 20% ethylacetate/hexane. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H), 3.62 (s, 3H),7.02 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.35 (dd, 1H, J=1.3, 8.2 Hz), 7.40(s, 1H), 10.47 (s, 1H). MS (ESI (−)) m/z 358/360 (M−H)⁻. Anal. calcd forC₁₆H₁₄N₃O₂Br, C, 53.4, H, 3.92, N, 11.7. Found, C, 52.6,H, 3.82, N,11.2.

EXAMPLE 145-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile

[0109] A solution of4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(70 mg, 0.2 mmol), PhCNPdCl(PPh₃)₂ (cat., 7 mg) and tetramethyltin (10eq, 0.35 g, 2 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. Thesolution was allowed to cool, poured into water (20 mL) and extractedwith ethyl acetate (3×5 mL). The combined organic layer was washed withbrine, dried over MgSO₄ and purified by flash column chromatography onsilica gel eluting with 30% ethyl acetate/hexane to give5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile(36 mg, 63%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H),1.97 (s, 3H), 3.56 (s, 3H), 6.87 (s, 1H), 7.00 (d, 2H, J=8.1 Hz), 7.28(dd, 1H, J=8.1, 1.6 Hz), 7.32 (s, 1H), 10.40 (s, 1H). MS (ESI (−)) 294(M−H)⁻. Anal. calcd for C₁₇H₁₇N₃O₂, C, 69.1, H, 5.8, N, 14.2. Found, C,69.1, H, 5.72, N, 14.0.

EXAMPLE 15 tert-Butyl5-cyano-2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-1-carboxylate

[0110] To a solution of 2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3] oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester(3.0 g, 8.2 mmol, 1 eq) in acetic anhydride (50 mL) was addedCu(NO₃)₂.2.5H₂O (1.04 g, 4.5 mmol, 0.55 eq). After the reaction mixturestirred at room temperature for 24 h, it was poured into saturatedaqueous sodium bicarbonate solution (100 mL) and extracted with ethylacetate (2×100 mL). The organic layers were combined, washed with water(50 mL) and brine (50 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification by flash column chromatography (20%ethyl acetate/hexane) on silica gel gave the product as a yellow solid(0.54 g, 16%). ¹H NMR (500 MHz, d₆-DMSO) δ 1.25 (s, 9H), 1.60 (s, 6H),6.97 (d, 1H, J=8.2 Hz), 7.38 (dd, 1H, J=1.8, 8.2 Hz), 7.49 (d, 1H, J=1.8Hz), 8.09 (s, 1H), 10.47 (s, 1H). MS (ESI (−)) [M−H]⁻=411. Anal. calcd.for C₂₀H₂₀N₄06: C, 58.25; H, 4.89; N, 13.59. Found: C, 58.72; H, 5.14,N, 13.39.

EXAMPLE 164-Amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile

[0111] A solution of 4-nitro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(0.4 g, 1.28 mmol) in ethanol/water (5:1, 20 mL) was treatedsequentially with zinc powder (2.5 wt, 1.0 g) and ammonium chloride (5wt, 2.0 g). The suspension was heated at 80° C. or 30 min, cooled toroom temperature, poured into water (30 mL) and extracted with ethylacetate (3×15 mL). The combined organic layer was washed with brine,dried over MgSO₄ and purified by flash column chromatography on silicagel eluting with ethyl acetate to give4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(0.29 g, 80%) as a yellow solid. ¹H NMR (500 MHz, d₆-DMSO) δ 1.63 (s,6H), 4.29 (s, 2H), 6.39 (s, 1H), 6.89 (d, 1H, J=8.1 Hz), 7.49 (s, 1H),7.52 (dd, 1H, J=8.1 and 2.3 Hz), 10.25 (s, 1H), 11.76 (s, 1H). MS (ESI(−)) m/z 281 (M−H)⁻. Anal. calcd for C₁₅H₁₄N₄O₂, C, 63.8, H, 5.00, N,19.9. Found, C, 63.7, H, 5.10, N, 19.82.

EXAMPLE 175-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile

[0112] To 4,4-Dimethyl-6-(5-cyano-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.3 g, 1.2 mmol, 1 eq) in acetic anhydride (7.3mL) was added Cu(NO₃)₂.2.5 H₂O (0.15 g, 0.65 mmol, 0.55 eq). After thereaction mixture stirred at room temperature for 2h, it was poured intosaturated aqueous sodium bicarbonate solution (50 mL) and extracted withethyl acetate (2×50 mL). The organic layers were combined, washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The residue crystallized fromdichloromethane/acetone to give the product as a yellow solid (48 mg,13%). The filtrate (0.3 g) was placed aside. ¹H NMR (300 MHz, d₆-DMSO) δ1.65 (s, 6H), 6.94 (d, 1H, J=8.3 Hz), 7.51 (s, 1H), 7.73(d, 1H, J=8.3Hz), 7.78 (s, 1H), 10.4 H), 13.84 (s, 1H). MS (ESI (−)) [M−H]⁻ m/z 311.Anal. calcd. for C₁₅H₁₂N₄O₄: C, 57.69; H, 3.87; N, 17.94. Found: C,57.91; H, 3.96, N, 17.41.

EXAMPLE 183-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile

[0113] To5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile(0.14 g, 0.45 mmol) in EtOH/H₂O (5:1, 20 mL:4 mL) was added Zn powder(0.35 g, 5.3 mmol) and NH₄Cl (0.70 g, 13 mmol) and the mixture washeated to 60° C. for 25 min. After cooling to room temperature andstirring 24 h, the reaction mixture was diluted with ethyl acetate (100mL) and filtered through a pad of celite. The filtrate was washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. Purification by flash column chromatography(60% ethyl acetate/hexane) on silica gel gave the product as an orangefoam (30 mg, 24%). ¹H NMR (500 MHz, d₆-DMSO) δ 1.63 (s, 6H), 5.01 (s,2H), 5.95 (d, 1H, J=2.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H,J=2.0, 8.3 Hz), 7.54 (d, 1H, J=2.0 Hz), 10.30 (s, 1H), 11.17 (d, 1H,J=2.5 Hz). MS (ESI) [M−H]⁻ m/z 281.

EXAMPLE 195-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile

[0114] To a solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile(1 eq, 0.15 g, 0.51 mmol) in THF (5 mL) at −78° C. was addedN-bromosuccinimide (1.1 eq, 0.1 g, 0.56 mmol). The solution was allowedto warm and stir for 16 hours. Pyridine (1 mL) was added and the mixturewas poured into water (15 mL), the layers were separated, the aqueouslayer was extracted with ethyl acetate (3×10 mL) and the combinedorganic layer was washed with brine, dried over MgSO₄ and concentratedin vacuo. The product,5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrilewas obtained by crystallization from 20% ethyl acetate/hexane as a whitecrystalline solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H), 1.93 (s,3H), 3.57 (s, 3H), 7.01 (d, 1H, J=8Hz), 7.31 (dd, 1H, J=1.95, 8Hz), 7.35(s, 1H), 1H). MS m/z (ESI (−)) 372/374 (M−H)⁻. Anal. calcd forC₁₇H₁₆N₃O₂, C, 54.6,H, 4.31, N, 11.2. Found, C, 54.8, H, 4.42, N, 11.1.

[0115] A solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile(0.11 g, 0.29 mmol), PhCNPdCl(PPh₃)₂ (cat., 11 mg) and tetramethyltin(10 eq, 0.53 g, 2.9 mmol) in HMPA (3 mL) was heated to 110° C. for 5d.The solution was allowed to cool, poured into water (20 mL) andextracted with ethyl acetate (3×15 mL). The combined organic layer waswashed with brine, dried over MgSO₄ and purified by flash columnchromatography on silica gel eluting with 30% ethyl acetate/hexane togive5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile(77 mg, 85%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.63 (s, 6H),1.87 (s, 3H), 2.49 (s, 3H), 3.50 (s, 3H), 6.99 (d, 1H, J=8.2 Hz), 7.25(dd, 1H, J=8.2, 1.4 Hz), 7.29 (s, 1H), 10.39 (s, 1H). MS (ESI (−)) 308(M−H)⁻. Anal. calcd for C₁₈H₁₉N₃O₄, C, 69.9, H, 6.19, N, 13.6. Found, C,68.8, H, 6.22, N, 12.9.

EXAMPLE 204-bromo-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile

[0116] To 4,4-Dimethyl-6-(5-cyano-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.625 g, 2.3 mmol, 1 eq) in THF (anhydrous, 60 mL)was added NBS (0.46 g, 2.5 mmol, 1.1 eq) at −78° C. After 1 h, thereaction was warmed to room temperature, poured into water (100 mL) andextracted with ethyl acetate (2×100 mL). The organic layers werecombined, washed with aqueous 10% sodium bisulfite solution (50 mL),water (50 mL) and brine (50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. Crystallization from 20% ethyl acetate/hexanegave the product (40 mg, 5%) as a white solid. The filtrate (0.5 g) wasplaced aside. ^(H NMR ()300 MHz, d₆-DMSO) δ 1.64 (s, 6H), 6.98 (d, 1H,J=8.2 Hz), 7.19 (d, 1 H, J=1.4 Hz), 7.57 (s, 1H), 7.62 (dd, 1H, J=1.4,8.3 Hz), 10.43 (s, 1H), 12.91 (s, 1H). MS (ESI) [M−H]⁻ m/z 344/346.Anal. calcd. for C₁₅H₁₂BrN₃O₂: C, 52.04; H, 3.49; N, 12.14. Found: C,51.4; H, 3.57, N, 11.59.

[0117] All publications cited in this specification are incorporatedherein by reference herein. While the invention has been described withreference to a particularly preferred embodiment, it will be appreciatedthat modifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

What is claimed is:
 1. A compound having the structure of formula 1:

wherein: T is S or absent; R₁ and R₂ are each, independently, hydrogen,alkyl, or substituted alkyl; or R₁ and R₂ are taken together form a ringselected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—; —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—,and —CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4 q=1-4 R₃ is hydrogen, OH, NH₂,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein: T isabsent; R₁ and R₂ are taken together form the ring —CH₂(CH₂)_(n)CH₂—; R₃is hydrogen; R₄ is hydrogen or halogen; R₅ is hydrogen or alkyl; R₆ ishydrogen or alkyl.
 3. The compound of claim 1, which is5-(2′-Oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrroleor a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, which is2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole or apharmaceutically acceptable salt thereof.
 5. The compound of claim 1,which is5-(2′-Oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrroleor a pharmaceutically acceptable salt thereof.
 6. A method of providingprogestational therapy to a mamrral in need thereof which comprisesadministering a progestationally effective amount of a compound havingthe structure of formula 1:

wherein: T is S or absent; R₁ and R₂ are each, independently, hydrogen,alkyl, or substituted alkyl; or R₁ and R₂ are taken together form a ringselected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—,and —CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4 R₃ is hydrogen, OH, NH₂,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 7. A method of treating or inhibitingbreast, uterine, ovarian, endometrial, or prostate cancer whichcomprises administering a compound having the structure of formula 1:

wherein: T is O, S,, or absent; R₁ and R₂ are each, independently,hydrogen, alkyl, or substituted alkyl; or R₁ and R₂ are taken togetherform a ring selected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂CMe₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—, and—CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4 R₃ is hydrogen, OH, NH₂, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₄ ishydrogen, halogen, CN, NH₂, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 8. A method of providing contraception ina mammal in need thereof, which comprises administering an effectiveamount of a compound having the structure of formula 1:

wherein: T is O, S,, or absent; R₁ and R₂ are each, independently,hydrogen, alkyl, or substituted alkyl; or R₁ and R₂ are taken togetherform a ring selected from the group consisting of —CH₂(CH₂)₂CH₂—,—CH₂CH₂CMe₂CH₂CH₂—, —O (CH₂)_(p)CH₂—,—O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—, and—CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4 R₃ is hydrogen, OH, NH₂, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₄ ishydrogen, halogen, CN, NH₂, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 9. A pharmaceutical composition, whichcomprises a compound having the structure of formula 1:

wherein: T is S or absent; R₁ and R₂ are each, independently, hydrogen,alkyl, or substituted alkyl; or R₁ and R₂ are taken together form a ringselected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—; —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—,and —CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4 R₃ is hydrogen, OH, NH₂,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof and a pharmaceutical carrier.